title: The impact of pathogenic mitochondrial DNA mutations on substantia nigra neurons.
abstract: Mitochondrial defects within substantia nigra (SN) neurons are implicated in the pathogenesis of Parkinson's disease. SN neurons show increased mitochondrial defects, mitochondrial DNA deletion levels, and susceptibility to such dysfunction, although the role of mitochondria in neuronal degeneration remains uncertain. In this study, we addressed this important question by exploring changes within the mitochondria of SN neurons from patients with primary mitochondrial diseases to determine whether mitochondrial dysfunction leads directly to neuronal cell loss. We counted the pigmented neurons and quantified mitochondrial respiratory activity, deficiencies in mitochondrial proteins, and the percentage of pathogenic mutations in single neurons. We found evidence of defects of both complex I and complex IV of the respiratory chain in all patients. We found that marked neuronal cell loss was only observed in a few patients with mitochondrial disease and that all these patients had mutations in polymerase gamma (POLG), which leads to the formation of multiple mitochondrial DNA deletions over time, similar to aging and Parkinson's disease. Interestingly, we detected α-synuclein pathology in two mitochondrial patients with POLG mutations. Our observations highlight the complex relationship between mitochondrial dysfunction and the susceptibility of SN neurons to degeneration and α-synuclein pathology. Our finding that the loss of SN neurons was only severe in patients with POLG mutations suggests that acquired mitochondrial defects may be less well tolerated by SN neurons than by inherited ones.
authors.affiliation: Newcastle University Centre for Brain Ageing and Vitality, Institute for Ageing and Health, and Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Reeve
authors.forename: Martin
authors.initials: M
authors.lastname: Meagher
authors.forename: Nichola
authors.initials: N
authors.lastname: Lax
authors.forename: Eve
authors.initials: E
authors.lastname: Simcox
authors.forename: Philippa
authors.initials: P
authors.lastname: Hepplewhite
authors.forename: Evelyn
authors.initials: E
authors.lastname: Jaros
authors.forename: Doug
authors.initials: D
authors.lastname: Turnbull
mesh_terms: D000328:Adult; D000375:Aging / Q000502:physiology; D002423:Cause of Death; D002452:Cell Count; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005116:Extrapyramidal Tracts / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000473:pathology; D020961:Lewy Body Disease / Q000473:pathology; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000473:pathology / Q000523:psychology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D017354:Point Mutation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013378:Substantia Nigra / Q000166:cytology / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D055815:Young Adult; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human